COPENHAGEN, Denmark—Checkpoint inhibition prolonged life when used as adjuvant therapy among patients with fully resected stage III malignant melanoma in the EORTC 18071 randomized phase III comparison of ipilimumab versus placebo. Findings were reported by Alexander M.M. Eggermont, M.D., Ph.D., Director General of the Comprehensive Cancer Center, Institut Gustave Roussy in Paris at the 2016 congress of the European Society for Medical Oncology—ESMO. He discusses his findings with the Audio Journal of Oncology’s Peter Goodwin.

Adjuvant Ipilimumab Brings Longer Survival with Stage III Melanoma

COPENHAGEN, Denmark—Checkpoint inhibition prolonged life, increased recurrence free survival and delayed metastasis when used as adjuvant therapy in patients who had fully resected stage III (regional lymph-node positive) malignant melanoma in the European Organization for Research and Treatment of Cancer (EORTC) 18071 randomized phase 3 comparison of ipilimumab versus placebo. Findings were reported at the 2016 congress of the European Society for Medical Oncology (ESMO). http://www.nejm.org/doi/full/10.1056/NEJMoa1611299?rss=searchAndBrowse#t=articleTop

The study found a 28 percent risk reduction for death in patients treated with ipilimumab, the fully human antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4) and enables the patient’s antitumor response.

“This is the first adjuvant study that has been done with an immune checkpoint inhibitor,” said first author Alexander M.M. Eggermont, MD, PhD, Director General of the Comprehensive Cancer Center at the Institut Gustave Roussy in Paris, who noted that previous data about the benefits of ipilimumab in melanoma had come from studies among patients with metastatic disease, among whom around 20 percent had been cured and were alive five to 10 years after beginning treatment.

In the EORTC 18071 study 951 patients from 99 centers in 19 countries were randomized to receive either ipilimumab at a high dose—10 milligrams per kilogram—every three weeks for the first 12 weeks (standard for metastatic disease) followed by one dose every 12 weeks for following three years. Patients in the control arm of the study received the same dosing, but with placebo. The primary endpoint was disease-free survival with overall survival and metastasis-free survival among the secondary endpoints.

All patients had regional lymph node metastatic disease and had undergone lymph node dissection, were tumor-free and were randomized within 12 weeks of their surgery.

Among the 471 patients treated with ipilimumab 251 (53.3 percent) discontinued treatment because of an adverse event as compared with only 22 patients (4.6 percent) in the placebo arm.

But ipilimumab was clearly effective with only 135 patients (28.7 percent) having recurrent disease within the follow-up period as compared with more than double this number, 282 (59.9 percent) of patients treated with placebo.

Only 63 patients (13.4 percent) treated with ipilimumab completed the full three year protocol as compared with 143 (30.2 percent) in the control arm.

“The data coming out of it—in terms of the primary endpoint recurrence-free survival— are significant,” Eggermont said. 40.8% of patients in the ipilimumab group remained free of recurrence five years after randomization compared with 30.3% in the placebo group—a hazard ratio for recurrence or death of 0.76 (P<0.001). “That means there is a 24 percent risk-reduction for [the composite of] relapse or death. So that’s highly significant,” he said.

For death alone adjuvant checkpoint inhibition brought an even bigger improvement. At 5.3 years follow-up the hazard ratio was 0.72 favoring ipilimumab treatment. “That means, in other words, a 28 percent risk-reduction for death,” he said. 162 patients had died in the ipilimumab arm but there were 52 more deaths in the placebo arm.

“So 65 percent of patients [were] still alive who had received ipilimumab, and only 54 percent—or 11 percent less—who had received placebo,” Eggermont said—evidence that checkpoint inhibition brought additional benefit when used earlier—before metastasis—although there were more immune-related adverse events.

Toxicity

But he said that there were grade 3 and 4 immune-related adverse events to which clinicians need to pay special attention. “Toxicities at the gastrointestinal level: diarrhea and full-blown colitis—which can lead to complications and perforations [from] which you can die—[were] seen in 16 percent of patients,” he said. And thyroiditis and hypothyroiditis were among the serious immune-related endocrine grade 3, 4 events. But he said the most important toxicity was knockout of the pituitary gland—hypophysitis, with affected nearly five percent of patients. “What that means is that you are on long-term—even life-long—hormone replacement therapy,” he said.

Additionally there was a 16 percent rate of hepatitis grade 3, 4 events, and he said that two patients had the neurologic immune-related adverse event— Guillain-Barre syndrome, of whom one was on a ventilator for so long that he developed multi-organ failure.

Eggermont said there were also five drug-related deaths on the trial. Three were in patients with colitis, one in a patient with myocarditis, and one more in the patient with Guillain-Barre syndrome.

“So you must instruct patients very carefully, and have a very careful surveillance systems so that you can see [toxicities] early—especially diarrhea and colitis,” he said, when ipilimumab should be stopped and treatments such as high-dose corticosteroids begun.

“And so we plea in favor of centralizing this adjuvant therapy to centers with sufficient experience and infrastructure to survey and instruct the patients to be proactive.”

He noted that using ipilimumab would be done within the large centers that have built up the experience. “I don’t think it’s a great idea that just anybody can prescribe ipilimumab and then fail in the follow-up of these patients.”

Eggermont’s report was discussed at the ESMO congress session by Olivier Michielin MD PhD, Head of the Melanoma Clinic in the Department of Oncology at Lausanne University in Switzerland, who is also Group Leader of the Swiss Institute of Bioinformatics in Lusanne, who said that this new EORTC study had contributed two important lessons, the first of which was clinical. “The benefit of CTLA4 blockade in the metastatic setting is indeed translating into the adjuvant [setting] and the sub-group analysis teaches us a lot about the specificities of ipilimumab compared to interferon,” he said.

Michielin was also impressed by the findings about immunological mechanisms. “Clearly we see for the first time that we can raise a T-cell response in a setting where there is only residual disease to trigger the right antigens. The final analysis shows that checkpoint blockade is effective in the adjuvant setting—a new historical landmark in our quest for the optimal treatment of melanoma.”

He said side effects were all important, which is why he emphasized the need to refer patients with melanoma to centers of excellence. But he pointed out that the therapeutic margin of ipilimumab was favorable compared to many other current treatments in cancer.

But Eggermont said the benefit from ipilimumab, albeit in the context of high toxicity, was a foretaste of what could lie ahead with the use of second-generation checkpoint inhibitors.

“We just fully accrued the trial of adjuvant pembrolizumab, the anti-PD1 drug. And we will be able to do the first analysis in 2018,” he said, adding that the advantage of harnessing anti-PD1 was that the toxicity profile was much more favorable, and yet the response rates—measured so far in metastatic disease—were higher.

While he acknowledged that the durability of therapeutic benefit from this anti-PD1 agents had yet to be assessed he was hopeful. “Expectations are that this is a very attractive adjuvant therapeutic, just like nivolumab, which is the other anti-PD1 agent,” he said. He was looking forward to trial results by the end of 2018.

The EORTC 18071 study with ipilimumab had established a clear superiority to interferon both in categories of patients who have microscopic disease only and in patients with palpable nodal disease, which he contrasted to the previous era. “In our experience—in some 3,000 melanoma patients—we have never seen any impact in palpable nodal disease with adjuvant interferons.